Management of

Sepsis and Septic Shock

Addis Ababa University School of Clinical Pharmacy

Gebre T/mariam (Bpharm, Mpharm) March 8, 2017 1

Outline

Background(Definitions)

Epidemiology

Risk factors

Clinical Features

Investigations and Diagnosis

Management modalities

Summary

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Objectives

At the end of this session, clinicians able to:

Define sepsis (new definition)

Determine predisposing factors for sepsis

Determine most suspected pathogens

Explain the approach of SOFA and qSOFA

Familiarize sepsis management modalities

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• Sepsis: A life threatening organ dysfunction caused by

a dysregulated host response to infection.

• Organ dysfunction is an acute change in total SOFA score

greater than 2(>2) points secondary to infection.

This new definition of sepsis 2016, called sepsis-3, stated that,

Sepsis is not simply infection + two or more SIRS criteria

Sepsis represents bad infection = leading to organ dysfunction

“Severe sepsis” is not helpful and eliminated[Singer et al, 2016].

Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) , 2016

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Cont’d

Septic shock: Subset of sepsis in which underlying circulatory,

cellular and metabolic abnormalities are associated with a

greater risk of mortality than sepsis alone.

• Clinically, this includes patients who fulfill the criteria

for sepsis despite adequate fluid resuscitation, patients

remain with a persistent hypotension requiring vasopressors

to maintain a mean arterial pressure(MAP) of >=65mmHg

and a serum lactate level >2mmol/L [Singer et al, 2016]. March 8, 2017 5

The ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992.

SIRS – Widespread inflammatory response

– Two or more of the following • Temp>38 C or <36 C

• Heart Rate >90 bpm

• Tachypnea, RR>20 or hyperventilation PaCO2 <32 mmHg

• WBC >12,000 or <4000 or presence of >10% bands, immature neutrophils.

Sepsis=SIRS + definitive source of infection

Severe Sepsis=Sepsis + organ dysfunction, hypoperfusion, or hypotension

Septic Shock: – Sepsis + hypotension despite fluids

– Perfusion abnormalities • Lactic acidosis

• Oliguria

• Multiple Organ System Failure: Abnormal function of two or more organs such that homeostasis cannot be achieved without intervention.

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Epidemiology According to the National Institute of General Medical Sciences (2012) the incidence of sepsis is increasing in the United States due to:

An aging population,

Increased chronic medical conditions,

Increased in antibiotic resistance,

Increase use of immunosuppressant’s and chemotherapy.

The case fatality rate for sepsis approximated 30% for sepsis, 50% for severe sepsis, and 80% for septic shock (Jawad etal., 2012).

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Sepsis in the emergency department in TikurAnbessa Specialized Hospital Addis

Ababa Ethiopia , By Tigist Zewdu, (2015) [Unpublished]

• Out of 4443 patients were evaluated in the ED

of TASH, 60 (1.35%) were diagnosed with sepsis.

• 68% and 32% of them were diagnosed with Septic shock and Severe Sepsis, respectively

• 56.7% were died in ED(mortality rate)

• 18.3% D/C

• 15% transferred to medical ward and

• 8.3% to ICU.

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Predisposing factors

• ICU admission (Nosocomial infection)

• Bacteremia

• Immunosuppression

• Advanced age and too young age

• Diabetes and Cancer

• Community acquired pneumonia

• Previous hospitalization

• Genetic defects

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Predisposing factors • Bacteremia – Patients with bacteremia often develop systemic

consequences of infection.

• In one study in Gondar Referral Hospital 19.3% of blood cultures, 95% of positive blood cultures were associated with sepsis and 68.8% were Staphylococcus aureus.

[Endris et al.,2014].

• Similarly, in JUSH, from a total of 95 suspected septc cases, 15 (15.8 %) were positive to 8 different types of bacteria.

• Gram +ve organisms were isolated in 53.3 % of these episodes with Staphylococcus aureus being the most frequent

• Gram –ve accounted 46.7 % with E.coli being the commonest isolate among Gram –ve bacteria.

[Abra et al.,2016]. March 8, 2017 10

Factors…cont’d • Nosocomial infection- ICU admission –50 % ICU

patients develop infection

• Age (≥65 years and very young under 1 year)

• Immunosuppression – Comorbidities that depress host-defense (eg, neoplasms, AIDS, and immunosuppressant medications

• A prospective study done in TASH, sowed that, HIV (40%), malignancy(30%) and diabetes and TB-HIV(11.7% and 8.3%)

• Genetic factors –defects of antibody production, or a lack of T cells, phagocytes, natural killer cells, ncreasing susceptibility microorganisms.

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Clinical Presentations • Specific to an infectious source (eg, cough dyspnea

may suggest pneumonia, pain and purulent exudate in a surgical wound may suggest an underlying abscess)

• Hypotension [SBP] <90 mmHg, [MAP] <70 mmHg, • Temperature >38.3 or <36ºC • HR >90 beats/min • Tachypnea, RR >20 breaths/min • Altered mental status • Ileus (absent bowel sounds; end-stage sign of

hypoperfusion) • Cyanosis, or mottling (may indicate shock)

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Investigations and Diagnostic Criteria

• Physical Examination…Vital Sign, mental status

• Blood Culture

• CBC

• Creatinine, bilirubin, lactate

• Urine output

• aPTT and INR

• Chest X-R(pneumonia)

• Ultrasound(fluid in abdomen)

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Blood Culture

• Obtain two sets of blood cultures before initiating any antibiotics empirically to determine the specific pathogen.

• This may be helpful to minimize drug resistance by using narrow spectrum of antibiotics

• However, organism is frequently not identified in up to 50 % of patients who present with sepsis nor is a positive culture required to make a decision regarding treatment with empiric antibiotics

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Old method of Sepsis Assessment(before sepsis-3) SIRS Criteria (≥ 2 meets SIRS definition)…. • Temp >38°C (100.4°F) or < 36°C (96.8°F) No Yes • Heart rate > 90 No Yes • Respiratory rate > 20 or PaCO₂ < 32 mm Hg No Yes • WBC > 12,000/mm³, < 4,000/mm³, or > 10% bands No Yes Sepsis Criteria (SIRS + Source of Infection)….. • Suspected or present source of infection No Yes Severe Sepsis Criteria (Organ Dysfunction, Hypotension or Hypoperfusion) • Lactic acidosis, SBP <90 or SBP drop ≥ 40 mm Hg of normal No Yes Septic Shock Criteria…. • Severe sepsis with hypotension, despite adequate fluid resuscitation No Yes Multiple Organ Dysfunction Syndrome Criteria… • Evidence of ≥ 2 organs failing No Yes

The ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1991/2001. March 8, 2017 15

SOFA

• SIRS is no longer criterion for sepsis.

• SIRS has been replaced qSOFA score.

• SOFA score is now used to clinically characterize septic patients.

• “Sepsis” and “septic shock” are the only 2 remaining categories.

• Lactate along with persistent hypotension is now a part of septic shock criteria,

• New definition of septic shock, a patient must have both hypotension (MAP< 65) and a lactate >2 mmol/L despite adequate fluid resuscitation.

New: Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) ,2016

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SOFA criteria SOFA= suspected infection plus a change in ≥2 of the following from baseline:

1. Respiratory – PaO2)/ FiO2 ratio

2. Hematology – Platelet count

3. Liver – Serum bilirubin

4. Renal – Serum creatinine (or urine output)

5. Brain – Glasgow Coma Scale.pdf

6. Cardiovascular – Hypotension and vasopressor requirement

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qSOFA criteria[New-2016-Sepsis-3,

1. Respiratory rate ≥22/minute

2. Altered mental status (GCS=<13)

3. Systolic blood pressure ≤100 mmHg

• qSOFA is born from SOFA that showed good predictive value of the simpler-to-attain variables

• It is easy as it has only three components

• Each are readily identifiable at the bedside

• No need of Laboratory findings

If two or more parameters are present, the risk of deterioration is high .

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Goal of therapy[pharmacotherapy[

• To eradicate the infection

• To reduce mortality

• To prevent complications

• To interrupt MODS

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Management Modalities

1. Respiratory Stabilization(oxygen]

2. IV Fluid resuscitation(aggressive)

3. Antibiotic administration(IV)..empirically

4. Vasopressors [unresponsive to Iv fluid]

5. Inotropic administration[unresponsive to vass.]

6. Red Blood transfusion[Hgb<7]

7. Glucocorticoid administration[refractory]

8. PPIs or H2BAs[stress ulcer Pxis]

9. Anticoagulants(VTE) March 8, 2017 23

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Oxygen (Respiratory stabilization)

• Supplemental oxygen should be supplied to all patients with sepsis and oxygenation must be monitored continuously with pulse oximetry.

• Intubation may be required to support the increased work of breathing

• In TASH, 25(41.7%) of patients from a total of 60 were failed to maintain oxygen saturation of which 23(38.3%) of were put on oxygen

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IV fluid resuscitation

• The rapid restoration of perfusion is predominantly achieved by the administration of IV fluids, usually crystalloids.

• IV Fluid …30ml/kg/*1-2L] over 30-60 minutes

• Volume status, tissue perfusion, blood pressure, and the presence or absence of pulmonary edema must be assessed before and after each.

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IV fluid… • Crystalloids as the fluid of choice for initial

resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock

• Use either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock

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• Only 31 (51.7%) of patients were given iv fluid from a total of 60 patient who were diagnosed with sepsis and from which 36(60%) of 60 patient were diagnosed as septic shock of which 5(13.9%) were not received iv fluid.

• 26 (43.3%) were received NS and

• Only 5( 8.3%) of the total 31 patient were received ringer lactate

Sepsis in the emergency department in Tikur Anbessa Specialized Hospital Addis Ababa Ethiopia , By Tigist Zewdu, (2015)

[Unpublished]

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Antibiotics • Earlier initiation of Broad spectrum IV antibiotic is

recommended (as soon as possible within 1 hour),

• It should be after obtaining appropriate cultures

• Early initiation of antibiotic can lower mortality

The choice of antibiotics can be complex and should consider:

• Patient's history ( Recent antibiotics received) comorbidities

• Clinical context (eg, HAP or CAP),

• Gram stain data, and

• Local resistance patterns March 8, 2017 30

Cont’d

• Empiric broad-spectrum therapy with one or more

antimicrobials for patients presenting with sepsis or

septic shock to cover all likely pathogens

• Broad-spectrum antibiotic coverage directed against

both gram-positive and gram-negative bacteria (eg,

Staphlococcus aureus, Klebsiella pneumoniae,

Streptocuccus pneumoniae

•

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Cont’d

• Empiric combination therapy should not be

administered for more than 3–5 days.

• Duration of therapy typically 7–10 days;

• Empiric antimicrobial therapy be narrowed once

pathogen identification and sensitivities are

established and/or adequate clinical improvement is

noted.

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Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic

Shock: 2016

• Empiric IV antimicrobials be initiated as soon as

possible within one hour for both sepsis and septic

shock broad enough to cover all likely pathogens

• Patients with nosocomial acquisition of infection are

prone to sepsis with MRSA and vancomycin-resistant

Enterococci (need to be consider).

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Cont’d Broad spectrum Beta lactam EMPIRIC ANTIBIOTIC CHOICES FOR COMMON INFECTIONS.pdf

• Piperacilin-Tazobactam

• Cefepime

• Meropenem

Anti MERSA

• Vancomycin or Linezolid

Supra gram –ve

• Piperacilin-Tazobactam

• Ceftazidime or Cefepime

• Meropenem or imipenem

• Ciprofloxacin

• Gentamycine

Atypical coverage

• Azitromycine

• Moxifloxacin

Anerobes coverage

• Metronidazole

• Clindamycin

• Meropenem or Imipenem

• moxifloxacin March 8, 2017 34

Cont’d • MRSA is a cause of sepsis in both hospitalized and non

hospitalized patients .

• Therefore, severely ill patients presenting with sepsis of

unclear etiology be treated with IV vancomycin

• Alternative agents to vancomycin

• Daptomycin for non-pulmonary MRSA,

• Linezolid, or

• Ceftaroline should be considered for patients with refractory or

virulent MRSA, or a contraindication to vancomycin

March 8, 2017 35

Cont’d

If Pseudomonas is an unlikely pathogen,

• Vancomycin+ Ceftriaxone or cefotaxime

If Pseudomonas is a possible pathogen, Vanco +

• Ceftazidime or Cefepime or

• Piperacillin-tazobactam or

• Ticarcillin-clavulanate or

• Imipenem or meropenem

• Gentamycine or amikacin or Aztreonam March 8, 2017 36

Cont’d • Vancomycin 15-20 mg IV q12 hrs with loading dose of 25-30

mg/kg IV, or Linezolid 600 mg PO/IV if contraindication to

Vancomycin, or Daptomycin 6 mg/kg IV q24 hrs if do not

suspect pulmonary source

+ Anti-Pseudomonal beta-lactam (Cefepime 2 g IV q8 hrs,

Ceftazidime 2 g IV q8 hrs, Piperacillin/Tazobactam 4.5 g IV q6

hrs, Imipenem 500 mg IV q6 hrs, or Meropenem 1 g IV q8 hrs)

+/- Anti-Pseudomonal Fluoroquinolone (Ciprofloxacin 400 mg

IV q12 hrs or Levofloxacin 750 mg IV q24 hrs), or

Aminoglycoside, or Aztreonam 1-2 g IV q8 hrs

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Cont’d….( Study in TASH) • 53(88.3%) of the total 60 patients who is diagnosed

as sepsis were Started on IV antibiotics of which:

• Only 11.7% of them started iv Abxs immediately

• 76.7% time of antibiotics not documented

• 11.7% were not received any antibiotics.

• 3.3% culture requested before initiation of Abxs

• 26.7%) were on ceftriaxone +metrindazole

• 23.3(%) on ceftriaxone alone

• 13.3%) on ceftriaxone + azitromycine

• 11.7% on vancomycine + ceftazidm[Tigist, 2015].

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Abx…cont’d(Study in JUSH and GRH)

• Ciprofloxacin was the most elective compared

with other drugs tested against the Gram positive

and Gram negative bacteria.

Another study in Godar Referal Hosptal:

• Vancomycine + Gentamycin and

• Ceftriaxone + Gentamycin

Were most effective Antibiotics

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Vasopressors

• IV vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema…to achieve MAP>=65mmHg

Norepinephrine 35-90mcg/min add based on

Vasopressin 0.03 units/min the achievement

Epinephrine 20-50mcg/min of MAP

Phenylephrine 200-300mcg/min >=65mmHg

In the study done in TASH, 13(21.7%) was on adrenaline.

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Cont’d Norepinephrine as the first choice vasopressor

Add vasopressin (up to 0.03 U/min) or

Add Epinephrine to norepinephrine with the intent of raising

MAP to target, or

Add vasopressin to decrease norepinephrine dosage.

Not recommend use of low-dose dopamine for renal protection

Dopamine as an alternative vasopressor agent to norepinephrine

only in highly selected patients (e.g., patients with low risk of

tachyarrhythmias and absolute or relative bradycardia)

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Additional Therapies

such as

• Inotropic therapy, and

• Blood transfusion are added, depending on

the response to :

• Based on the evidence for myocardial

dysfunction, and

• Presence of anemia, respectively

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Inotropic therapy

• Are as additional therapy for those patients who have

refractory shock who also have diminished cardiac output

[hypoperfusion despite adequate fluid loading and the use

of vasopressor agents]

• Dobutamine OR Dopamine

• In TASH, 35 (58.3%) patients were put on inotropic agent

from a total of 36 patient who diagnosed with septic shock

and of which 22(36.7%) of them were put on dopamine

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Red blood cell transfusions

• Reserved for patients with Hgb <7 gm/dl

• Exceptions include suspicion of concurrent

hemorrhagic shock or active myocardial ischemia

• RBC transfusion occur only when hemoglobin

concentration decreases to < 7.0 g/dL in adults

severe hypoxemia, or acute hemorrhage

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Glucocorticoids

• Glucocorticoids have long been investigated as

therapeutic agents in sepsis because the

pathogenesis of sepsis involves an intense and

potentially deleterious host inflammatory response.

• Hydrocortisone should be added to the treatment

regimen for patients with septic shock that is

unresponsive to IV fluids and vasopressor therapy.

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Glucocorticoids…

• Hydrocortison 50 mg IV QID , or 100 mg IV bolus

followed by an infusion of 10 mg/hour for 7 days.

• Once hemodynamically stable, hydrocortisone

should then be tapered over a few days (to avoid

rebound hypotension).

• No role for steroids in sepsis in the absence of

shock, nor a role for high-dose steroids in sepsis

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Venous thromboembolism prophylaxis

• Pharmacologic prophylaxis (unfractionated heparin

[UFH] or low-molecular-weight heparin [LMWH])

against VTE in the absence of contraindications to the

use of these agents

• LMWH rather than UFH for VTE prophylaxis in the

absence of contraindications to the use

of LMWH(stronger recommendation).

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Stress ulcer prophylaxis

• Stress ulcer prophylaxis be given to

patients with sepsis or septic shock who have risk factors

for GI bleeding

• Using either proton pump inhibitors (PPIs)

or histamine-2 receptor antagonists (H2RAs) when stress

ulcer prophylaxis is indicated

• In contrast some studies recommend against stress ulcer

prophylaxis in patients without risk factors for GI bleeding

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IDSA-Comment on Sepsis-3 • Published: January 2017 • "2016 International Guidelines for Management of Sepsis and Septic Shock" • The importance of guidelines for identifying and treating sepsis and septic

shock cannot be understated and IDSA recognizes the enormous positive impact the Society of Critical Care Medicine’s (SCCM) Surviving Sepsis Campaign has had on its prevention and treatment. However, IDSA ultimately withdrew its endorsement of the 2016 guideline based on an inability to reach a timely agreement regarding specific antibiotic recommendations including stewardship, not the overall value of the guideline itself.

• IDSA collaborates with SCCM on several clinical practice guidelines and greatly values these opportunities. We hope that we will have an opportunity to participate in the development of the next update of the Surviving Sepsis Campaign guideline and in promoting appropriate handling of this dangerous consequence of infectious diseases.

• *For information, please contact the SCCM or the Surviving Sepsis Campaign.

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References 1. Freund Y, Lemachatti N, Krastinova E, et al. Prognostic Accuracy of Sepsis-3 Criteria for

In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department. JAMA 2017; 317:301.

2. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:775.

3. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:762.

4. Raith EP, Udy AA, Bailey M, et al. Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA 2017; 317:290.

5. Endris, M, Takele, Y, Woldeyohannes, D, Tiruneh, M, Mohammed, R, Moges, F, Lynen, L, Jacobs, J, van Griensven, J & Diro, E , 'Bacterial sepsis in patients with visceral leishmaniasis in Northwest Ethiopia, BioMed Research International, vol 2014, pp. 361058. DOI: 10.1155/2014/361058.

6. Abera K,Tesfaye K, Zewudneh S, Deresse D and Andualem H: Bacterial Profle of Adult Sepsis and their Antmicrobial Susceptbility Patern at Jimma University Specialized Hospital, South West Ethiopia: Health science Journal,2016:10:(2)3 .

7. Sepsis in the emergency department in Tikur Anbessa Specialized Hospital Addis Ababa Ethiopia , By Tigist Zewdu (2015) [Unpublished].

8. Uptodate Last updated Jan 11, 2017[online].

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Cont’d

9. Andrew Rhodes, Laura E. Evans, Waleed Alhazzani, Mitchell M. Levy, Massimo Antonelli, et al :Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016, Intensive Care Med (2017) 43:304–377

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Thank You

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